Man?s total environment including diet, lifestyle and environmental chemicals has a major impact on health. The effects of environmental chemicals are most dramatic when they alter a regulatory system that amplifies the toxicity. We will examine effects of toxins and disease on lipid chemical mediators or oxylipins. Deleterious effects also are more global when the environmental chemicals alter a system fundamental to many cells and organs. Thus, we will investigate how environmental chemicals increase endoplasmic reticulum stress resulting in negative and often chronic outcomes in multiple organs. Natural epoxyfatty acids (EpFA) are a component of a regulatory system that maintains homeostasis. We are using inhibitors of the soluble epoxide hydrolase (sEHI) to stabilize these beneficial EpFA. A variety of environmental chemicals such as triclosan and nonsteroidal anti- inflammatory drugs damage these pathways enhancing disease states. sEHI restore the homeostatic systems leading to improvement in many disease models including for diabetes, heart failure, neuropathic and inflammatory pain, fibrosis and toxicities. Recently, we reported sEHI beneficial for treating cancer as well as Parkinson?s and depression. With the flexibility offered by the RIVER program, we will evaluate the relationships among these disease states, determine biochemical mechanisms, and monitor the levels of EpFA and other chemical mediators. Based on this knowledge we will develop cellular and biochemical biomarkers of health and disease particularly for diseases related to endoplasmic reticulum stress. We will continue providing the biochemical and analytical tools developed for this work for the broad scientific community. These tools include clones and proteins of the sEH enzyme, sEH inhibitors as probes and drugs, novel bioassays, antibodies and nanobodies, synthetic standards of regulatory lipids, and of course analytical methods. We will expand our testing of the hypothesis that toxicity and disease can be altered by pharmacological and nutritional intervention both in house and with collaborators. In particular, we will expand our recent studies that by stabilizing natural omega 6 and omega 3 fatty acid epoxides, sEHI can prevent and reverse symptoms of depression, Parkinson?s disease and other CNS disorders and block tumor resurgence and metastasis caused by cell debris from cancer chemotherapy and resection. Thus, we will test the hypothesis that the mitochondrial?ROS?ER stress axis is a common mechanism in the onset of many toxicities and pathological outcomes and that these effects can be prevented or reversed by increasing epoxyfatty acids. While carrying out the above research we continue and expand our work to reduce barriers to entering the oxylipin research field by providing service and reagents. Our research will be coupled with a training and outreach component to encourage collaboration and free information exchange in the oxylipin discipline. The work is transformative in emphasizing chronic rather than short-term toxicities, illustrating a new mechanism of toxicity in ER stress, and in exploring approaches to prevent the toxicities by manipulating endogenous chemical mediators.